Novel phosphorous containing steroid mimics

ABSTRACT

The present invention discloses novel steroid mimics wherein a tri- or tetravalent phosphorous atom is isosterically substituted at any one of the seventeen positions occupied by the carbon atom in the steroidal skeleton, and wherein each adjacent position to the phosphorous is either unsubstituted or optionally substituted by nitrogen or an oxygen atom to satisfy the valency of said phosphorous atom. The invention is illustrated schematically below using both aromatic and non-aromatic steroids. Although the isosteric substitution  
                 
phosphorous atom in the above structures 3-7 is indicated at 13, 14, and 17 positions, it is to be noted that the phosphorous can be substituted at any one of the seventeen positions in non-aromatic or eleven positions in aromatic steroids. The phosphorous atom may be trivalent or tetravalent, and may be radioactive or non-radioactive. The adjacent atoms, X, Y, or Z may be carbon, oxygen, or nitrogen. Other positions in the steroid mimics 3-8 may be optionally substituted alkyl, aryl, or other polar or non-polar functional groups to optimize biodistribution, receptor binding, and pharmacokinetic properties.

FIELD OF THE INVENTION

This invention relates to heteroatom-containing compositions which mimicthe molecular framework of a steroid. In particular, the presentinvention discloses novel phosphasteroids wherein the phosphorous atomis isosterically substituted at the positions previously occupied by acarbon atom in the steroidal skeleton.

BACKGROUND OF THE INVENTION

It is to be noted that throughout this application various publicationsare referenced by Arabic numerals within brackets. Full citations forthese publications are listed at the end of the specification. Thedisclosures of these publications are hereby incorporated by referencein their entireties into this application in order to more fullydescribe the state of the art to which this invention pertains.

Targeted delivery of medically useful elements to a particular sitecontinues to be of considerable importance in diagnosis, prognosis, andtherapy of various lesions [1]. For example, gadolinium is usedextensively for magnetic resonance imaging (MRI); barium and iodine areused for X-ray computed tomography (CT); technetium, indium, lutetium,samarium, and iodine are used for planar imaging and single photonemission tomography (SPECT); gallium and fluorine are used for positronemission tomography (PET); rhenium, samarium, yttrium, lutetium, andphosphorous are used for radiotherapy; and europium, ruthenium, andrhenium have potential utility for optical imaging and opticaltomography. In particular, ³²P, a β-emitting radioisotope ofphosphorous, has considerable radiotherapeutic potential for variouslesions depending on its incorporation into a selected molecularcarrier. For example, incorporation of ³²P into a steroid receptorbinding molecules such as androgens, estrogens, antiestrogens,progestins, and the like may be useful for the treatment of steroidreceptor positive tumors; incorporation into somatostatin receptorbinding molecules such as octreotide may be useful for the treatment ofneuroendocrine tumors; or incorporation into carbohydrate receptorbinding molecules such as selectins or integrins may be useful forinflammatory process.

Conventional bioconjugate method of delivering diagnostic andtherapeutic agents, both small molecules and macromolecules, such asdrugs, enzymes, metal complexes, fluorescent and radioactive probes, andthe like to a particular tissue involves the external attachment ofthese agents to a targeting carrier whose size is typically considerablylarger than the effector molecules. This methodology has been referredto as “external bifunctional” approach, and has been quite successful inthe development of in vitro diagnostic products. However, one of mostvexing problems in bioconjugate chemistry with respect to thedevelopment of in vivo diagnostic and therapeutic agents is that theexternal attachment of a radionuclide complex to small molecule carriersalmost always impedes receptor binding [2]. This problem can be readilyresolved by the use of macromolecular carriers such as antibodies orreasonably large peptides where the epitope topology is not muchaltered. An epitope is a specific region of the molecule that isactually involved in the adhesion of the effector and carrier throughthe intermolecular forces. Unfortunately, macromolecular bioconjugatespresent many problems with respect to bioavailability, pharmacokinetics,and biodistribution. Moreover, for nuclear medicine applications, theexternal bifunctional agents presents additional radiotoxicity ofcritical non-target tissues such as the liver and the kidney due tounacceptably large percent injected dose to and poor clearance fromthese organs. In order to address both of the aforementioned problems,viz., receptor binding and bioavailability, we have previouslyintroduced a general concept referred to as ‘internal bifunctional’approach or ‘small molecule drug mimics’ wherein the medically usefulatom is integrated into a known effector molecule thereby preserving theoverall size and shape of the original molecule. This approach was basedon the well established principle that antibodies, enzymes, andreceptors are multispecific, i.e., they will bind to molecules that aretopologically similar to the natural antigens, substrates, or ligands.The concept of radionuclide metal ion based drug mimics wasindependently proposed by Rajagopalan [3, 4] and Katzenellenbogen [5].Katzenellenbogen's work on steroid mimics confirmed experimentally thatthe idea of integrating a metal ion into natural receptor ligands is aviable strategy for targeted delivery of diagnostically andtherapeutically useful radionuclides to target tissues [2, 5-7].

Our previous work on steroid mimics focused on isosteric substitution ofmetal ions such as technetium and rhenium into various positions inaromatic and non-aromatic steroidal framework as illustratedschematically by generic structures 1 and 2 [4]. A considerabledifficulty with respect to incorporating a metal ion into a carbonframework is the deviation

from tetrahedral geometry. For example, Tc(V) and Re(V) oxidation stateforms a square pyramidal geometry, which may contribute to reducedreceptor binding capability. Furthermore, ¹⁸⁶Re obtained from thegenerator is not carrier free, i.e., only 5% is in the radioactive form;the rest of the material is the non-radioactive (‘cold’) isotope ofrhenium. Therefore, this presents a formidable challenge to preparesteroid mimics with very high specific activity needed forradiotherapeutic purposes. In contrast, ³²P can be obtained in acarrier-free from. Thus, there is a need in the art to prepare novelradiodiagnostic and radiotherapeutic steroidal compositions with highspecific activity and having high affinity for steroid receptors.Accordingly, the present invention focuses phosphorous-based steroidmimics. Although phosphasteroids have been known for sometime [8, 9],surprisingly there has not been much activity in developing them intomedically useful products. Introducing a phosphorous atom into thesteroidal skeleton solves two key problems: (a) the preservation oftetrahedral geometry, and (b) the preparation of steroid mimics havingvery high specific activity. In addition, steroids are transportedacross cell membrane from the blood to the cytoplasm via steroid bindingproteins (SBP) [10]. Since the phosphorous containing steroid mimics ofthe present invention have same topology at the original steroids, it isanticipated that the mimics will bind to SBP and transported into thecell in the same manner as the native steroid molecules.

SUMMARY OF THE INVENTION

The present invention discloses novel steroid mimics wherein a tri- ortetravalent phosphorous atom is isosterically substituted at any one ofthe seventeen positions occupied by the carbon atom in the steroidalskeleton, and wherein each adjacent position to the phosphorous iseither unsubstituted or optionally substituted by nitrogen or an oxygenatom to satisfy the valency of said phosphorous atom. The number ofadjacent substitutions depends on whether a secondary, tertiary, orquaternary position is substituted; substitution at the secondary centerrequires two substitutions, and tertiary and quaternary centers requirethree substitutions. The invention is illustrated schematically belowusing both aromatic and

non-aromatic steroids. Although the isosteric substitution ofphosphorous atom in the above structures is indicated at 13, 14, and 17positions, it is to be noted that the phosphorous can be substituted atany one of the seventeen positions in non-aromatic or eleven positionsin aromatic steroids. The phosphorous atom may be trivalent ortetravalent, and may be radioactive or non-radioactive. The adjacentatoms, X, Y, or Z may be carbon, oxygen, or nitrogen. Other positions inthe steroid mimics 3-8 may be optionally substituted alkyl, aryl, orother polar or non-polar functional groups to optimize biodistribution,receptor binding, and pharmacokinetic properties. In particular, 7α,11β, and 17α positions in steroids have been shown to tolerate bulkysubstituents, including metal complexes [11-13], and the substitutionsat these positions in the steroid mimics of this invention are alsocontemplated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses novel aromatic phosphorous steroid mimiccompositions of Formulas 9-12,

wherein P is —P— or —P═O. X and Y are independently —O— or —NR⁴. R¹ toR³ are independently selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; hydroxyl; carboxyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl;C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkxoycarbonyl. R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonylalkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.

A preferred embodiment of the present invention is represented byFormula 9,

wherein P is —P— or —P═O. X is —O— or —NR⁴. R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl. R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C_(-C) ₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo,trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀arylalkyl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl,C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl.

Another preferred embodiment of the present invention is represented byFormula 10,

wherein P is —P— or —P═O. X is —O— or —NR⁴. R² and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; hydroxyl;carboxyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl;C₅-C₁₀ aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl,C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl. R⁴ is selected from thegroup consisting of hydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.

Another preferred embodiment of the present invention is represented byFormula 11,

wherein P is —P— or —P═O. X and Y are independently —O— or —NR⁴. R¹ andR² are independently selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; carboxyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl;C₅-C₁₀ aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl,C₁-C₁₀ alkoxyl, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl. R⁴ is selected from thegroup consisting of hydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkxoylcarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.

Another preferred embodiment of the present invention is represented byFormula 12,

wherein P is —P— or —P═O. X is —O— or —NR⁴. R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl. R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo,trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀arylalkyl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl,C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl.

The compounds of the present invention can be prepared by the methodswell known in the art. Compounds belonging to Formula 9 can be preparedby the according to the method

similar to the one for the specific steroid mimic 16 outlined inScheme 1. The key step in this process is the construction of thetetrahydroisoquinoline intermediate 11, which can be either accomplishedby Bischer-Napieralski cyclization followed by reduction, or by one-stepPictet-Spengler cyclization. Substitutions at the 7, 11, and 17positions can be introduced by selecting appropriate starting materials.For example, 7 substituted derivatives can be prepared3-methoxyphenylalaine; 11 substituted derivatives can be prepared fromα-cyanoacetate derivatives; and 17 substituted derivatives can beprepared by elaborating the 17-hydroxymethyl group in 16.

Compounds belonging to Formula 10 can be prepared according to themethod similar to the one for the specific steroid mimic 20 outlined inScheme 2. The amine 13 can be

prepared by standard methods from 5-hydroxy-2-nitrobenzoic acid. Theunprotected derivative of lactone 18, the 'Geissman-Waiss lactone, hasused extensively as a key intermediate for the synthesis ofpyrrolizidine alkaloids. The original synthesis of this lactone isreported by Geissman and Waiss [14], which is incorporated herein byreference in its entirety.

Compounds belonging to Formula 11 can be prepared by the according tothe method similar to the one for the specific steroid mimics 23 and 24outlined in Scheme 3. The ester 21 can prepared by acylating6-methoxy-2-tetralone with dimethyl carbonate by the method similarVerba et al. [15], which is incorporated herein by reference in itsentirety.

Compounds belonging to Formula 12 can be prepared by the according tothe method similar to the one for the specific steroid mimic 27 outlinedin Scheme 4. The acid chloride 24 can be prepared from3-hydroxyhydrocinnamic acid. The condensation of 24 and 25 can also beeffected via the enamine acylation method.

Compounds of the present invention may exist as as a single stereoisomeror as mixture of enantiomers and diastereomers whenever chiral centersare present. Individual stereoisomers can be isolated by the methodswell known in the art: diastereomers can be separated by standardpurification methods such as fractional crystallization orchromatography, and enantiomers can be separated either by resolution orby chromatography using chiral columns.

The phosphasteroids of the present invention is useful in therapy anddiagnostic imaging of respective steroid receptor containing lesions.The present invention is also applicable for the development ofcompounds with full or partial agonistic, antagonistic, and inverseagonistic properties at the respective steroid receptors at differenttissues for diagnostic and therapeutic purposes.

The compounds of the present invention can be administered in the pureform, as a pharmaceutically acceptable salt derived from inorganic ororganic acids and bases, or as a pharmaceutically ‘prodrug.’ Thepharmaceutical composition may also contain physiologically tolerablediluents, carriers, adjuvants, and the like. The phrase“pharmaceutically acceptable” means those formulations which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and animals without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well-known inthe art, and are described by Berge et al. [16], incorporated herein byreference. Representative salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,chloride, bromide, bisulfate, butyrate, camphorate, camphor sulfonate,gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, maleate, succinate, oxalate, citrate, hydrochloride,hydrobromide, hydroiodide, lactate, maleate, nicotinate,2-hydroxyethansulfonate (isothionate), methane sulfonate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, tartrate, phosphate,glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lithium,sodium, potassium, calcium, magnesium, aluminum, ammonium, tetramethylammonium, tetraethylammonium, trimethylammonium, triethylammonium,diethylammonium, and the like.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals enterally or parenterally in a solid, liquid,or vapor form. Enteral route includes, oral, rectal, topical, buccal,and vaginal administration. Parenteral route intravenous, intramuscular,intraperitoneal, intrasternal, and subcutaneous injection or infusion.The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompositions can also be delivered via an implantable drug deliverydevices such as micro miniature mechanical pumps, osmotic pumps, orother similar kind of reservoirs.

The active compound is mixed under sterile conditions with apharmaceutically acceptable carrier along with any needed preservatives,excipients, buffers, or propellants. Opthalmic formulations, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention. Actual dosage levels of the activeingredients in the pharmaceutical formulation can be varied so as toachieve the desired therapeutic response for a particular patient. Theselected dosage level will depend upon the activity of the particularcompound, the route of administration, the severity of the conditionbeing treated, the sensitivity of the target lesions, and prior medicalhistory of the patient being treated. However, it is within the skill ofthe art to start doses of the compound at levels lower than required toachieve the desired therapeutic effect and to increase it graduallyuntil optimal therapeutic effect is achieved. The total daily dose ofthe compounds of this invention administered to a human or lower animalmay range from about 0.0001 to about 1000 mg/kg/day. For purposes oforal administration, more preferable doses can be in the range fromabout 0.001 to about 5 mg/kg/day. If desired, the effective daily dosecan be divided into multiple doses for purposes of administration;consequently, single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose.

The phrase “therapeutically effective amount” of the compound of theinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated, the severity of the disorder; sensitivity of the disorder;activity of the specific compound employed; the specific compositionemployed, age, body weight, general health, sex, diet of the patient;the time of administration, route of administration, and rate ofexcretion of the specific compound employed, and the duration of thetreatment. The compounds of the present invention may also beadministered in combination with other drugs if medically necessary.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof. These compositions can also contain adjuvants such aspreserving, wetting, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride and the like.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin. Properfluidity can be maintained, for example, by the use of coating materialssuch as lecithin, by the maintenance of the required particle size inthe case of dispersions, and by the use of surfactants. In some cases,in order to prolong the effect of the drug, it is desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable medium just prior to use.

Dosage forms for topical administration include powders, sprays,ointments and inhalants. Solid dosage forms for oral administrationinclude capsules, tablets, pills, powders and granules. In such soliddosage forms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol, and silicic acid; b) binders suchas carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents. Solid compositions of a similar type mayalso be employed as fillers in soft and hard-filled gelatin capsulesusing such excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like. The solid dosage forms oftablets, dragees, capsules, pills and granules can be prepared withcoatings and shells such as enteric coatings and other coatingswell-known in the pharmaceutical formulating art. They may optionallycontain opacifying agents and may also be of a composition such thatthey release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof. Besides inert diluents, the oral compositions may alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Compounds of thepresent invention can also be administered in the form of liposomes. Asis known in the art, liposomes are generally derived from phospholipidsor other lipid substances. Liposomes are formed by mono- ormulti-lamellar hydrated liquid crystals which are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether. Methods to form liposomes are known in the art [16],incorporated herein by reference.

The compounds of the present invention can also be administered to apatient in the form of pharmaceutically acceptable ‘prodrugs.’ The term“pharmaceutically acceptable prodrugs” as used herein represents thoseprodrugs of the compounds of the present invention which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and lower animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the invention.

Prodrugs of the present invention may be rapidly transformed in vivo tothe parent compound of the above formula, for example, by hydrolysis inblood. A thorough discussion is provided in the literature [18, 19],incorporated herein by reference.

The Examples presented below describe preferred embodiments andutilities of the invention and are not meant to limit the inventionunless otherwise stated in the claims appended hereto. The descriptionis intended as a non-limiting illustration, since many variations willbecome apparent to those skilled in the art in view thereof. It isintended that all such variation within the scope and spirit of theappended claims be embraced thereby. Changes can be made in thecomposition, operation, and arrangement of the method of the presentinvention described herein without departing from the concept and scopeof the invention as defined in the claims.

EXAMPLE 1 Preparation of Phosphasteroid Mimic 12

Step 1.

A solution of cyanoacetic acid (22 mmol) and tritheylamine (45 mmol) inmethylene chloride (20 mL) is stirred and cooled to 0° C.Isobutylchloroformate (22 mmol) is added dropwise to the above mixtureat such a rate that the internal temperature is maintained at 0-5° C.and the entire mixture is allowed to stir at this temperature for 1hour. A solution of 3-methoxyphenylethylamine (20 mmol) in methylenechloride (10 mL) is added in portions and the entire mixture is thenallowed to stir at ambient temperature for 4 hours. The reaction mixtureis poured onto water and the organic layer is separated, washed with 5%HCl, saturated sodium bicarbonate, and brine. The organic layer is driedover anhydrous magnesium sulfate, filtered, and the filtrate evaporatedin vacuo to give the desired cyanoacetamide derivative, which can beused as such for the next step.

Step 2.

A solution of the cyanoacetamide (10 mmol) from Step 1 in anhydrous,ethanol-free chloroform (20 mL) is treated with phosphorous oxychloride(12 mmol) and the mixture is stirred and heated under reflux for 16hours. The reaction mixture is diluted with chloroform (20 mL) andpoured onto saturated sodium bicarbonate solution (100 mL). The organiclayer is separated, washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate evaporated in vacuo to give thedesired dihydroisoquinoline derivative, which is purified bychromatography or recrystallization.

Step 3.

A solution of the dihydroisoquinoline from (10 mmol) from Step 2 isdissolved in anhydrous methanol (30 mL), treated with magnesium metal(12 mmol) and stirred and heated under reflux for 16 hours. The reactionmixture is evaporated in vacuo and the residue is treated with water (50mL), and extracted with methylene chloride (50 mL). The organic layer isseparated, washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate evaporated in vacuo to give the desiredcyanomethyl tetrahydroisoquinoline derivative, which is purified bychromatography or recrystallization.

Step 4.

A solution of the cyano derivative (10 mmol) from Step 3 is dissolved inmethylene chloride (20 mL), is treated with di-t-butyldicarbonate (12mmol) and stirred at ambient temperature for 16 hours. The solvent isevaporated in vacuo, and the crude material is purified bychromatography or recrystallization.

Step 5.

A solution of the nitrile derivative (10 mmol) from Step 4 is dissolvedin methanol (30 mL), and carefully treated with Adam's catalyst (PtO₂)(200 mg) and glacial acetic acid (1 mL). The mixture is hydrogenated atabout 50 psi (3.6 atm) for 16 hours. The reaction mixture is filteredthrough Celite and the filtrate is evaporated in vacuo. The crudematerial is purified by chromatography or recrystallization.

Step 6.

A mixture of the amine (10 mmol) from Step 5, dimethyl 2-ketomalonate(11 mmol), and acetic acid (5 mL) is carefully treated with sodiumcyanoborohydride (12 mmol). The entire mixture is stirred at ambienttemperature for 16 hours, and thereafter the solvent is evaporated invacuo. The residue is treated with water (50 mL) and methylene chloride(50 mL). The organic layer is separated, washed with saturated sodiumbicarbonate followed by brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate evaporated in vacuo to give the desireddiester, which is purified by chromatography or recrystallization.

Step 7.

A solution of the diester (10 mmol) from Step 6 in anhydroustetrahydrofuran (25 mL) is stirred and cooled to 0° C. under inertatmosphere. A solution of lithium aluminum hydride (1M in THF) is addeddropwise such that the temperature is maintained at 0-5° C. After theaddition, the mixture is heated under reflux for 4 hours after whichtime the reaction is again cooled to 0° C. Requisite amount of ice-coldwater is added dropwise while maintaining the temperature at 0-5° C.Once all the excess lithium aluminum hydride is decomposed, the reactionmixture is diluted with additional THF (30 mL) and treated withanhydrous sodium sulfate and kept at ambient temperature for 30 minutes.The mixture is then filtered, and the filtrate evaporated in vacuo. Theresidue is dissolved in methylene chloride (20 mL), treated withtrifluoroacetic acid (10 mL), and kept at ambient temperature for 2hours. Thereafter, the solvent and excess TFA is removed by evaporationin vacuo to give the desired aminodiol which is used as such for thenext step.

Step 8.

A solution of the aminodiol (10 mmol) from Step 7 in anhydrous,ethanol-free chloroform (20 mL) is treated with phosphorous oxychloride(12 mmol) and the mixture is stirred and heated under reflux for 16hours. The reaction mixture is diluted with chloroform (20 mL) andpoured onto saturated sodium bicarbonate solution (100 mL). The organiclayer is separated, washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate evaporated in vacuo to give thedesired the methyl ether of the steroid mimic, which is purified bychromatography or recrystallization.

Step 9.

A mixture of the methyl ether (10 mmol) from Step 8 in anhydrous,dimethylformamide (10 mL) and lithium propylmercaptide (20 mmol) isheated at 80-90° C. for 16 hours. Excess solvent is removed byevaporation in vacuo, and the residue is treated with 5% HCl (10 mL) andwater (50 mL) and extracted with methylene chloride (50 mL). The organiclayer is separated, washed thoroughly with water, dried over anhydroussodium sulfate, filtered, and the filtrate evaporated in vacuo to givethe desired phosphorous steroid mimic 12, which is purified bychromatography or recrystallization.

EXAMPLE 2 Preparation of Phosphasteroid Mimic 16

Step 1:

A mixture of 3-hydroxypyrrolidine-2-acetic acid lactone (10 mmol) anddi-t-butyldicarbonate (11 mmol) in methylene chloride (20 mL) is stirredat ambient temperature for 16 hours. The solvent is evaporated in vacuo,and the crude material is purified by chromatography orrecrystallization.

Step 2.

A mixture of the Boc-protected lactone (10 mmol) from Step 2,2-amino-5-hydroxybenzylalcohol dimethyl ether (10 mmol), and p-TsOH (0.5mol) in anhydrous dimethylformamide (10 mL) and lithium propylmercaptide(20 mmol) is heated at 80-90° C. for 16 hours. Excess solvent is removedby evaporation in vacuo, and the residue is treated with 5% HCl (10 mL)and water (50 mL) and extracted with methylene chloride (50 mL). Theorganic layer is separated, washed thoroughly with water, dried overanhydrous magnesium sulfate, filtered, and the filtrate evaporated invacuo to give the desired phosphorous steroid mimic, which is purifiedby chromatography or recrystallization.

Step 3.

A solution of the diester (10 mmol) from Step 6 in anhydroustetrahydrofuran (25 mL) is stirred and cooled to 0° C. under inertatmosphere. A solution of diborane (30 mL) (1M in THF) is added dropwisesuch that the temperature is maintained at 0-5° C. After the addition,the mixture is heated under reflux for 16 hours after which time thereaction is again cooled to 0° C. Requisite amount of ice-cold water isadded dropwise while maintaining the temperature at 0-5° C. Once all theexcess diborane is decomposed, the reaction mixture is treated withwater (30 mL) and extracted with methylene chloride. The organic layeris separated, washed with brine, dried over anhydrous sodium sulfate,filtered, and the filtrate evaporated in vacuo. The crude product ispurified by chromatography or recrystallization.

Step 4:

The purified Boc-protected compound from Step 3 is dissolved inmethylene chloride (20 mL), treated with trifluoroacetic acid (10 mL),and kept at ambient temperature for 2 hours. Thereafter, the solvent andexcess TFA is removed by evaporation in vacuo to give the desiredaminodiol which is used as such for the next step.

Step 5.

A solution of the dibenzyl ether from Step 4 (10 mmol) from Step 4 isdissolved in methanol (30 mL), and carefully treated with 10% Pd—C (200mg). The mixture is hydrogenated at about 50 psi (3.6 atm) for 4 hours.The reaction mixture is filtered through Celite and the filtrate isevaporated in vacuo. The residue is treated with saturated sodiumbicarbonate (20 mL) and methylene chloride (30 mL). The organic layer isseparated, washed thoroughly with water, dried over anhydrous sodiumsulfate, filtered, and the filtrate evaporated in vacuo. The residueused as such for the next step.

Step 6.

A solution of the aminodiol (10 mmol) from Step 5 in anhydrous,ethanol-free chloroform (20 mL) is treated with phosphorous oxychloride(12 mmol) and the mixture is stirred and heated under reflux for 16hours. The reaction mixture is diluted with chloroform (20 mL) andpoured onto saturated sodium bicarbonate solution (100 mL). The organiclayer is separated, washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate evaporated in vacuo to give thedesired steroid mimic 16, which is purified by chromatography orrecrystallization.

EXAMPLE 3 Preparation of Iphosphasteroid Mimic 19

Step 1:

The procedure is identical to Step 1 in Example 1, except that malonicacid monomethyl ester is used instead of cyanoacetic acid; all otherreagents and solvents are the same. The crude unsaturated ester ispurified by chromatography or recrystallization.

Step 2:

A mixture of the unsaturated ester from Step 1 (10 mmol) and sodiumazide (30 mmol) in methanol is treated with trifluoroacetic acid (30mmol) and allowed to stir at ambient temperature for 16 hours. If thereaction is not completed by this time additional quantities of sodiumazide and trifluoroacetic acid may be added. The reaction mixture ispoured onto saturated sodium bicarbonate and extracted with methylenechloride. The organic layer is separated, washed with brine, dried overanhydrous magnesium sulfate, filtered, and the filtrate evaporated invacuo to give the desired azide, which is purified by chromatography orrecrystallization.

Step 3.

A solution of the azidoester (10 mmol) from Step 2 in anhydroustetrahydrofuran (25 mL) is stirred and cooled to 0° C. under inertatmosphere. A solution of lithium aluminum hydride (1M in THF) is addeddropwise such that the temperature is maintained at 0-5° C. After theaddition, the mixture is heated under reflux for 4 hours after whichtime the reaction is again cooled to 0° C. The workup of the reaction iscarried out exactly as described in Step 7, Example 1. The crudematerial is used as such for the next step.

Step 4.

A mixture of the amine from Step 3 (10 mmol), 2-iodoethanol (12 mmol),and finely-ground anhydrous potassium carbonate (20 mmol) in glyme (20mL) is heated under reflux for 6 hours. The reaction mixture is thencooled and filtered. The filtrate is evaporated in vacuo to give thedesired aminodiol, which is purified by chromatography orrecrystallization.

Step 5.

The aminodiol from Step 4 is phosphorylated by the same proceduredescribed in Step 8, Example 1 to give the desired methylether of thesteroid mimic, which is purified by chromatography or recrystallization.

Step 6:

The final conversion of the methyl ether to the desired steroid mimic 19is accomplished in the same manner as described in Step 9, Example 1.

EXAMPLE 4 Preparation of Phosphasteroid Mimic 24

Step 1:

A solution of diisopropylamine (15 mmol) in anhydrous THF is stirred andcooled to −30° C. in an inert atmosphere. Thereafter n-BuLi (17 mmol) (2M solution in hexane) is then added via a syringe. The solution isstirred at about −30° C. for 30 minutes and treated with2-benzyloxycyclopentanone (11 mmol). The entire mixture is stirred atthis temperature for 30 minutes and treated with5-benzyloxy-2-nitrophenylacetyl chloride (10 mmol). The mixture isallowed to reach ambient temperature and stirred at this temperature for4 hours. The reaction mixture is poured onto water and extracted withmethylene chloride. The organic layer is separated, washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrateevaporated in vacuo to give the desired nitro compound, which ispurified by chromatography or recrystallization.

Step 2.

A solution of the nitro derivative (10 mmol) from Step 1 is dissolved inmethanol (30 mL), and carefully treated with Adam's catalyst (PtO₂) (200mg) and glacial acetic acid (1 mL). The mixture is hydrogenated at about50 psi (3.6 atm) for 16 hours. The reaction mixture is filtered throughCelite and the filtrate is evaporated in vacuo. The crude amino diol ispurified by chromatography or recrystallization.

Step 3.

A solution of the aminodiol (10 mmol) from Step 2 in anhydrous,ethanol-free chloroform (20 mL) is treated withphenylphosphodichloridate (12 mmol) and the mixture is stirred andheated under reflux for 16 hours. The reaction mixture is diluted withchloroform (20 mL) and poured onto saturated sodium bicarbonate solution(100 mL). The organic layer is separated, washed with brine, dried overanhydrous magnesium sulfate, filtered, and the filtrate evaporated invacuo to give the desired the steroid mimic 24, which is purified bychromatography or recrystallization.

References

-   1. Wagner, H. N.; Szabo, M. D.; Buchanan, J. W. (Eds.). Principles    of Nuclear Medicine. Saunders: Philadelphia, 1995.-   2. Chi, D. Y.; O'Neil, J. P.; Anderson, C. J.; Welsh, M. J.;    Katzenellenbogen, J. A. Homodimeric and heterodimeric bis(amino    thiol) oxometal complexes with rhenium(V) and technetium(V). Control    of heterodimeric complex formation and an approach to metal    complexes that mimic steroid hormones. J. Med. Chem. 1994, 37,    928-937.-   3. Rajagopalan, R. Nitrogen sulfur ligands as opiate receptor drug    mimics. U.S. Patent 1994: U.S. Pat. No. 5,330,737.-   4. Rajagopalan, R. Metal containing steroid mimics and ligands    useful in the preparation thereof. U.S. Patent 1997: U.S. Pat. No.    5,602,236.-   5. Chi, D. Y.; Katzenellenbogen, J. A. Selective formation of    heterodimeric aminothiol oxometal complexes of rhenium(V). J. Am.    Chem. Soc. 1993, 115, 7045-7046.-   6. Hom, R. K.; Katzenellenbogen, J. A. Synthesis of oxorhenium(V)    complex mimic of a steroidal estrogen. J. Org. Chem. 1997, 62,    6290-6297.-   7. Skaddan, M. B.; Katzenellenbogen, J. A. Integrated oxorhenium(V)    complexes as estrogen mimics. Bioconjugate. Chem. 1999, 10, 119-129.-   8. Bodlaski, R., et al. An efficient synthesis of the entantiomeric    17-phosphasteroid system. J. Org. Chem. 1982, 47(11), 2219-2220.-   9. Symmes, C.; Morris, J.; Quin, L. D. A new synthesis of    phosphasteroids employing the McCormack cycloaddition for    construction of the D-ring. Tetrahedron Letters 1977, 4, 335-338.-   10. Miller, W. R. In Estrogen and Breast Cancer, Medical    Intelligence Unit; R. G. Landes Co. and Chapman and Hall: New York,    1996.-   11. Skaddan, M. B.; Wust, F. R.; Katzenellenbogen, J. A. Synthesis    and binding affinities of novel Re-containing 7α-substituted    estradiol complexes: Models for breast cancer imaging agents. J.    Org. Chem. 1999, 64, 8108-8121.

12. DiZio, J. P.; Anderson, C. J.; Davidson, A.; Ehrhardt, G. I.;Carlson, K. E.; Welsh, M. J.; Katzenellenbogen, J. A. Technetium- andrhenium-labeled progestins: Synthesis, receptor binding, and in vivodistribution of an 11β-substituted progestin labeled with technetium-99and rhenium-186. J. Nucl. Med. 1992, 33, 558-569.

-   13. El Amouri, H.; Vessieres, A.; Vichard, D.; Top, S.; Gruselle,    M.; Jaouen, G. Syntheses and affinities of novel    organometallic-labeled estradiol derivatives: A structure-activity    relationship. J. Med. Chem. 1992, 35, 3130-3135.-   14. Geissman, T. A.; Waiss, A. C. Total synthesis of    (±)retronecine. J. Am. Chem. Soc. 1993, 115, 7045-7046.-   15. Verba, J; Carrie, R. Tetrahedron 1983, 39(24), 4163-4174.-   16. S. M. Berge et al. J. Pharmaceutical Sciences 1977, 66, 1 et    seq.-   17. T. Higuchi and V. Stella. Pro-drugs as Novel Delivery    Systems, V. 14. A.C.S. Symposium Series, 1987.-   18. Edward B. Roche (Ed.). Bioreversible Carriers in Drug Design.    American Pharmaceutical Association and Pergamon Press: New York    1987.-   19. Prescott, Ed., Methods in Cell Biology, Volume XIV, pp. 33 et    seq. Academic Press, New York, 1976.

1. A compound of Formula 9,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 2. The compound of claim1, wherein P is —P═O; X is —O— or —NR⁴; R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; and R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀alkoxycarbonyl.
 3. The compound of claim 1, wherein P is —P═O; X is —O—or —NR⁴; R¹ to R³ are hydrogen; and R⁴ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀acyl, or C₁-C₁₀ alkoxycarbonyl.
 4. The compound of claim 1, wherein P isa radioactive isotope of phosphorous.
 5. A compound of Formula 10,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R² and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 6. The compound of claim5, wherein P is —P═O; X is —O— or —NR⁴; R² and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; and R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀alkoxycarbonyl.
 7. The compound of claim 5, wherein P is —P═O; X is —O—or —NR⁴; R² and R³ are hydrogen; and R⁴ is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ acyl, or C₁-C₁₀ alkoxycarbonyl.
 8. The compound of claim 5,wherein P is a radioactive isotope of phosphorous.
 9. A compound ofFormula 11,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R¹ and R² are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 10. The compound ofclaim 9, wherein P is —P═O; X is —O— or —NR⁴; R¹ and R² areindependently selected from the group consisting of hydrogen; C₁-C₁₀alkyl; C₅-C₁₀ aryl unsubstituted or substituted with C₁-C₁₀ alkyl,hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; and R⁴ is selected from the groupconsisting of hydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl,and C₁-C₁₀ alkoxycarbonyl.
 11. The compound of claim 9, wherein P is—P═O; X is —O— or —NR⁴; R¹ and R² are hydrogen; and R⁴ is hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ acyl, or C₁-C₁₀ alkoxycarbonyl.
 12. The compound ofclaim 9, wherein P is a radioactive isotope of phosphorous.
 13. Acompound of Formula 12,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 14. The compound ofclaim 13, wherein P is —P═O; X is —O— or —NR⁴; R¹ and R³ areindependently selected from the group consisting of hydrogen; C₁-C₁₀alkyl; C₅-C₁₀ aryl unsubstituted or substituted with C₁-C₁₀ alkyl,hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; R² is C₁-C₁₀ alkyl or C₁-C₁₀ alkoxyl;and R⁴ is selected from the group consisting of hydrogen; C₁-C₁₀ alkyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀ alkoxycarbonyl.
 15. Thecompound of claim 13, wherein P is —P═O; X is —O— or —NR⁴; R¹ and R³ arehydrogen; R² is C₁-C₁₀ alkoxyl; and R⁴ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀acyl, or C₁-C₁₀ alkoxycarbonyl.
 16. The compound of claim 13, wherein Pis a radioactive isotope of phosphorous.
 17. A method of performing adiagnostic or a therapeutic procedure comprising administering to anindividual an effective amount of compound of Formula 9,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 18. The method of claim17, wherein P is —P═O; X is —O— or —NR⁴; R¹ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; and R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀alkoxycarbonyl.
 19. The method of claim 17, wherein P is —P═O; X is —O—or —NR⁴; R¹ to R³ are hydrogen; and R⁴ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀acyl, or C₁-C₁₀ alkoxycarbonyl.
 20. The method of claim 17, wherein P isa radioactive isotope of phosphorous.
 21. A method of performing adiagnostic or a therapeutic procedure comprising administering to anindividual an effective amount of compound of Formula 10,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R² and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 22. The method of claim21, wherein P is —P═O; X is —O— or —NR⁴; R² and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; and R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀alkoxycarbonyl.
 23. The method of claim 21, wherein P is —P═O; X is —O—or —NR⁴; R² and R³ are hydrogen; and R⁴ is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ acyl, or C₁-C₁₀ alkoxycarbonyl.
 24. The method of claim 21,wherein P is a radioactive isotope of phosphorous.
 25. A method ofperforming a diagnostic or a therapeutic procedure comprisingadministering to an individual an effective amount of compound ofFormula 11,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R¹ and R² are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and R⁴ is selected from the group consisting ofhydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 26. The method of claim25, wherein P is —P═O; X is —O— or —NR⁴; R¹ and R² are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; and R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ acyl, and C₁-C₁₀alkoxycarbonyl.
 27. The method of claim 25, wherein P is —P═O; X is —O—or —NR⁴; R¹ and R² are hydrogen; and R⁴ is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ acyl, or C₁-C₁₀ alkoxycarbonyl.
 28. The method of claim 25,wherein P is a radioactive isotope of phosphorous.
 29. A method ofperforming a diagnostic or a therapeutic procedure comprisingadministering to an individual an effective amount of compound ofFormula 12,

wherein P is —P— or —P═O; X is —O— or —NR⁴; R⁴ to R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; carboxyl;C₁-C₁₀ hydroxyalkyl; C₁-C₁₀ alkoxycarbonyl; C₅-C₁₀ aryl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl; and C₅-C₁₀ arylalkylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; R⁴ is selected from the group consisting of hydrogen;C₁-C₁₀ alkyl; C₁-C₁₀ acyl; C₁-C₁₀ hydroxyalkyl; C₅-C₁₀ arylunsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, cyano, halo, trihaloalkyl, carboxyl, C₁-C₁₀ acyl, C₁-C₁₀hydroxyalkyl, amino, C₁-C₁₀ alkylamino, C₁-C₁₀ dialkylamino, and C₁-C₁₀alkoxycarbonyl; and C₅-C₁₀ arylalkyl unsubstituted or substituted withC₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, cyano, halo, trihaloalkyl,carboxyl, C₁-C₁₀ acyl, C₁-C₁₀ hydroxyalkyl, amino, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, and C₁-C₁₀ alkoxycarbonyl.
 30. The method of claim29, wherein P is —P═O; X is —O— or —NR⁴; R¹ and R³ are independentlyselected from the group consisting of hydrogen; C₁-C₁₀ alkyl; C₅-C₁₀aryl unsubstituted or substituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀alkoxyl, trihaloalkyl, and halo; C₅-C₁₀ arylalkyl unsubstituted orsubstituted with C₁-C₁₀ alkyl, hydroxyl, C₁-C₁₀ alkoxyl, trihaloalkyl,and halo; R² is C₁-C₁₀ alkyl or C₁-C₁₀ alkoxyl; and R⁴ is selected fromthe group consisting of hydrogen; C₁-C₁₀ alkyl; C₁-C₁₀ hydroxyalkyl;C₁-C₁₀ acyl, and C₁-C₁₀ alkoxycarbonyl.
 31. The method of claim 29,wherein P is —P═O; X is —O— or —NR⁴; R¹ and R³ are hydrogen; R² isC₁-C₁₀ alkoxyl; and R⁴ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ acyl, or C₁-C₁₀alkoxycarbonyl.
 32. The method of claim 29, wherein P is a radioactiveisotope of phosphorous.